DE2104580A1 - Alpha-3-acylureido benzyl penicillins antibacterial agents esp - against klebsiella - Google Patents

Abstract

Penicillin of the following general formula and their non-toxic salts, including the various stereochem. forms derived from CIn this formula A is XCONY-, or where E is O or S, and X,Y,Z and Q may be chosen from a considerable, no. of designated gps. for which the original must be consulted; B is Ph (opt. substd. by alkyl, alkoxy, alkylthio or halogen) or thienyl. Among prepd. cpds. D-alpha-(3-acetyl-3-methylureido)benzylpenicillin and D-alpha-(imidazolidine-2-one-2-one-1-yl) carbonylamino) benzylpenicillin. The cpds are active against Gram +ve and Gram -ve organisms, partic. against Klebsiella.

Description

New penicillins, processes for their production and their use as medicaments and feed additive The present invention relates to new ones Penicillins, processes for their production, as well as their use as antibacterial Agents, nutritional additives in animal feed and as therapeutic agents in poultry and animals as well as in humans in the treatment of gram-positive and gram-negative Bacteria and in particular from infectious diseases caused by Klebsiella bacteria.

Antibacterial agents such as ampicillin (U.S. Patent 2,985,648), have proven themselves in the therapy of infections caused by gram-positive and gram-negative Bacteria proved very effective. However, you cannot get Klebsiella infections to combat effectively. Carbenicillin (U.S. Patents 3,142,673 and 3,282,926) is only effective in humans in infections caused by Klebsiella bacteria if it in persistent high dosage that can only be achieved by infusion, is given.

The present invention relates to such 6 - («- 3-Acylureidoacetamido) -penicillanic acids, in which the hydrogen atom of the nitrogen atom in the 3-position the ureido group is substituted by other radicals (F), the one on the N3 atom of the ureido group located acyl radical is an aminocarbonyl radical, in which there is a nitrogen atom Hydrogen atom - its amino group is monosubstituted by a radical (G) is - and where the two radicals F and G are connected to one another to form a ring are.

6 - («- 3-Acylureidoacetamido) -penicillanic acids are in the Dutch U.S. Patents 69,01646 and 69,08909, U.S. Patents 3479339, '3483188,3481922, and U.S. Patents 3479339,' 3483188,3481922, and U.S. Patents 3479339 German Offenlegungsschrift 1 959 920, but all in these have 3-acylureidophenylacetamidopenicillanic acids described and claimed in patents in the acylureido group on the nitrogen atom in the 3-position Hydrogen atom. The presence of this hydrogen atom and the absence of one other substituents at this point of the acylureido group result in part inevitably from the other similar synthetic route of these penicillins.

The present invention also relates to a method of manufacture such compounds useful in the treatment of infections caused by gram-positive and Gram-negative germs, in particular from Klebsiella aerobacter strains, at lower levels Dosage are able to provide valuable help.

According to the invention, a process for the preparation of compounds of the general formula has now been established where A is a group E is oxygen or sulfur, Q is a divalent group of the type: GG G 1,2,3 or 4 G10 drew or 1 C (C) 1 or 2 G GG p and g = 0, 1, 2 or 3 p (M) 8 LP p + g = 1, 2 or 3 GG % iu or 1 PF of the 1st G <- C = C y GGG Gl rp and g = 0 or 17 p + g = 0 or 1 G -II 1 R2 where G is hydrogen or lower alkyl, R1 and R2 hydrogen, nitro, nitrile, di-lower alkylamino, di-lower alkylaminocarbonyl, lower alkanoylamino, lower alkoxycarbonyl, lower alkanoyloxy, lower alkyl, lower alkoxy, sulfamyl, chlorine, bromine, iodine, fluorine or trifluoromethyl, the arrow in the divalent group to express that the connection of the two free valences of with the two N atoms of the group not arbitrarily, but in the manner indicated by the arrow, M is a group G or 13 5 VG 2,3,4 or 5 GEG > 1 @ (<. Gp 8 jP p and g = 0, 1 or 21 p bp + g = 2 or 3 j 6 G p G1 J means B denotes phenyl or phenyl or thienyl substituted by lower alkyl, lower alkoxy, lower alkylthio or halogen, and which, with respect to the center of chirality C *, can be in the two possible R and S configurations and as mixtures of the resulting diastereomers and of non-toxic pharmaceutically acceptable salts thereof Compounds created by using compounds of the general formula II or condensation products of compounds of general formula II with carbonyl compounds such as acetone (USA Patent No. 3,198,804), of general formula III or compounds of the general formulas IV and V where B and G have the meaning given above and R *, R5 and R6 are alkyl with up to 6 carbon atoms, with compounds of the general formula VI where E and Q have the meaning given above and W is halogen or azide, in the case of using the compounds of the general formula II and III in anhydrous or water-containing solvents in the presence of a base, in the case of using the compounds of the general formulas IV and V in anhydrous and hydroxyl group-free solvents with or without the addition of a base at a temperature in the range from about -20 ° C to + 50 ° C for implementation.

Among the non-toxic, pharmaceutically acceptable ones mentioned above Salts include salts of the acidic carboxyl group, such as sodium, potassium, magnesium, calcium, Aluminum and ammonium salts and non-toxic substituted ammonium salts with amines such as di- and tri-lower alkylamines, procaine, dibenzylamine, N, N'-dibenzylethylenediamine, N-benzylp-phenylethylamine, N-methyl- and N-ethylmorpholine, l-ephenamine, dehydroabietylamine, N, N'-bis-dehydroabietylethylenediamine, N-lower alkylpiperidine and other amines, which have been used to form salts of penicillins.

By the term "lower alkyl" is used in the present invention both a straight chain and a branched alkyl group with up to 6 carbon atoms Understood. In connection with other groups as in 11Di-lower alkylamino "refers the term "-lower alkyl-" applies only to the alkyl portion of the group in question.

Is used as a starting material for the synthesis of the invention Penicillins compounds of the general formulas II or III and combines them with compounds of the general formula VI, these reactions can be carried out, for example, in mixtures of water with such organic Solvents with water are miscible, such as acetone, etrahydrofuran, dioxane, acetonitrile, dimethylformamide, Perform dimethyl sulfoxide or isopropanol. The pH of the reaction mixture is maintained during this by adding bases or using buffer solutions, for example between 6.5 and 8.0. The reaction according to the invention can also be used in another Carry out a pH range, for example between 4.5 and 9.0 or at pH 2.0 - 3.0. It is also possible to carry out the reaction in water-immiscible solvents, for example chloroform or methylene chloride with the addition of preferably triethylamine, To carry out diethylamine or N-ethylpiperidine. Furthermore, the reaction in a mixture of water and a water-immiscible solvent such as B. ether, chloroform, methylene chloride, carbon disulfide, isobutyl methyl ketone, Run ethyl acetate, benzene, it is advisable to stir vigorously, and the pII value by adding base or using buffer solutions between 4.5 and 9.0 or e.g. 2.0 and 3.0.

The reactants can be used in equimolecular amounts be made to react. However, it may be appropriate to use either of the two To use reactants in excess for purification or purification of the desired penicillin and to increase the yield. For example you can use the reactants of the general formulas II or III with an excess Use from 0.1 to 0.3 molar equivalents and thus less decomposition of the reactant of the general formula VI in the aqueous solvent mixture reach. The excess of the reactant of the general formulas II or III can be because of the good good solubility in aqueous mineral acids with Work up Easily remove the reaction mixture. On the other hand, you can also take advantage of this the reactants of the general formula VI with an excess of, for example Use 0.1 to 1.0 molar equivalents. This will make the reactants the general Formula II or III better exploited and used as a side reaction in water-containing Solvents decomposition of the reactants of the general formula V compensated. Since the compounds of the general formula V rapidly convert to neutral ureas or thioureas in water, which can be easily removed, the purity of the penicillins is hardly affected.

The amount of bases used is, for example, due to the desired compliance set a certain pH. Where pH measurement and adjustment are not carried out or not because of the lack of sufficient amounts of water in the diluent possible or useful, in the case of using the compounds of the general Formula II or III, preferably 2 molar equivalents of base, in the case of using the Compounds of the general formulas IV or V either no base at all or preferably 1 molar equivalent of base added.

The work-up of the reaction batches for the preparation of the inventive Penicillins and their salts take place consistently in the same way as for penicillins in general known way.

Those used as the starting material in the present invention Compounds of the general formula II or III can with regard to the configuration at the asymmetrical center in the side chain (: C *> in the D = R form or L = S-shape occur. They are in German Patent No. 1 156 078, in the U.S. Patent Nos. 3,342,677, 3,157,640, 2,985,648, 3,140,282, and 3,198,804, in which South African Patent No. 68/0290 and (an anhydrous form) in the United States patent No. 3,144,445. All crystal forms and configurations of the connections of the general formula II or III are used as starting material for the inventive Reaction suitable.

The configuration of the asymmetric centers of the 6-aminopenicillanic acid core in the compounds of the general formula II, III, IV and V should be with the corresponding asymmetric centers of 6-aminopenicillanic acid, e.g. fermentative processes obtained must be identical.

Is used as a starting material for the synthesis of compounds of the general formula IV or V and sets these substances with compounds of the general Formula VI to, it must be in anhydrous and hydroxyl-free solvents, for example in methylene chloride, chloroform, benzene, tetrahydrofuran, acetone or dimethylformamide work. The addition of bases is not necessary here, but you can do this improve the yield and purity of the products in individual cases. The reverse However, an effect is also possible. Any bases added must either tertiary amines such as pyridine or triethylamine or steric hindrance secondary amines that are difficult to acylate, such as dicyclohexylamine. The number of usable Bases is therefore hardly limited.

As with most chemical reactions, they can be higher or lower Temperatures than those given in the examples can be used. But if you go considerably beyond the values given there, are becoming increasingly common Side reactions take place which reduce the yield or the purity of the products adversely affect. On the other hand, excessively lowered reaction temperatures reduce the rate of reaction is so great that a reduction in the yield can occur. There are therefore reaction temperatures in the range from -200C to + 50 ° C are preferred, where a temperature of about OOC to + 200C is particularly preferred.

The representation of the compounds used as starting material of general formula IV and V is in Dutch Patent No. 68/18057 described.

The representation of the compounds to be used as starting material of the general formula VI is described in Examples No. 1 B and 4 C, or can be carried out in the same way as described in the examples.

The chemotherapeutic effectiveness of the new penicillins was tested in vivo and in vitro. In the following table 1 the in vitro inhibition values (MIC) are given in U / ml nutrient medium. The determination was carried out in liquid medium in the tube serial dilution test, the reading taking place after incubation for 24 hours at 37 ° C. The MIC is given by the turbidity-free tube in the dilution series. A complete medium of the following composition was used as the growth medium: Lab Lemco (OXOID) 10 g peptone (DIFCO) 10 g NaCl 3 g D (+) dextrose (MERCK) 10 g buffer pH 7.4 1000 ml Table 1 MIC in U / ml bacterial strains ampicillin Penicillin example 1 E. coli 14 <0.78 1.56 E. coli A 261) 400 400 E. coli C 165 6.25 6.25 E. coli 183/58 75 50 Prot. Vulg. 1017> 4oo 12 Prot. Vulg. 3400> 400 25 Klebsiella K 10 100 50 Klebsiella 63 100 50 Pseudom. aerug. Bo> 400 6.25 Pseudom. aerug. Whale) 400 12.5 ter Staph. aur. 1777 E 100 200 Staph. aur. 133 (0.78 (0.78 Streptoc. faec. ATCC 979 25 25 The animal experiments (see Table 2) were carried out with white mice of the strain CF1. The infection took place intraperitoneally with the bacteria specified in each case.

Table 2 Number of surviving mice in% (after i.p.

Infection and subcutaneous therapy) after the specified number of Days.

Bacterial strains penicillin dose *) 1st 2nd 3rd 5th day E.coli C 165 example 1 A 80 80 80 80 E. coli C 165 Carbenicillin A 70 50 50 50 Prot.vulg. 1017 I example 1 A 70 50 50 50 Carbenicillin A 50 50 50 50 Ampicillin A O 0 0 0 Example 4 B 100 100 100 100 Klebsiella 63 Example 1 B 70 30 0 Carbenicillin B O Ampicillin B O Cephalothin B O Example 4 C 100 100 40 10 Pseudm. aer. Whale example 1 D 100 20 20 20 ter Carbenicillin D 80 20 20 20 Ampicillin D O Cephalothin D O Dose A = 37 500 U / kg 30 and 90 min. After infection Dose B = 75,000 U / kg 30 and 90 in. After Infection dose C = 150,000 U / kg 30 and 90 minutes after infection, dose D = 150,000 U / kg 0.5, 2, 4 and 6 hours after infection The spectrum of activity includes both gram-positive and gram-negative bacteria. The special advantage of the penicillins according to the invention lies in the fact that they can be used in vitro and in animal experiments bacteria from the Klebsiella group that are resistant to ampicillin and carbenicillin aerobacter, against ampicillin-resistant Proteus bacteria and against Pseudomonas aeruginosa and enterococci are effective.

The penicillins according to the method can be used alone or in combination with a pharmaceutically acceptable carrier substance according to the usual pharmaceutical Procedure to be formulated and administered. For oral administration can it in the form of tablets, which for example additionally starch, lactose, certain Types of clay, etc. may contain, or-in the form of capsules, drops or Granules, given alone or together with the same or equivalent additives will. They can also be taken orally in the form of juices or suspensions that are suitable for such purposes may contain customary flavor corrections or colorings will.

Furthermore, the penicillins according to the method can by parenteral Application, e.g. intramuscular, subcutaneous or intravenous, possibly as a continuous drip infusion, administered. In the case of parenteral administration, this happens on best as a sterile solution that contains other components of the solution, such as sodium chloride or may contain glucose to make the solution isotonic. To such solutions To prepare, you can expediently these penicillins in the form of dry ampoules use. For oral and parenteral administration, a dosage of 25,000 is Up to 1 million U / kg body weight / day appropriate.

You can take it as a single dose or as a continuous drip infusion or as well Spread over several doses. For a local treatment one can use the procedure according to the procedure Prepare and use penicillins as ointments or powder.

The following examples are intended to illustrate the invention without limiting it limit. When calculating the analysis values, the water content is taken into account. The <x-aminobenzylpenicillin used in the examples contained about 14 water, but you can just as well contain other amounts of water or anhydrous «-Aminobenzylpenicillin rcomp. U.S. Patent 3,144,445 7 may employ.

Example 1 A. D - (Imidazolidin-2-on-1-yl-carbonylamino) -benzylpenicillin: 14 parts by weight of D-cc-aminobenzylpenicillin (ampicillin) were dissolved in 80 Aigem aqueous Tetrahydrofuran (130 parts by volume) suspended and dropwise with stirring at 200C so much triethylamine is added (approx. 6.5 parts by volume) that just a clear solution arose and the pH was between 7.5 and 8.2 (glass electrode). One cooled now to 0 ° C. and the solution of 5.4 parts by weight of N-chlorocarbonylimidazolidin-2-one was added dropwise in 25 Vol.T1n. absolute tetrahydrofuran with ice cooling and vigorous stirring within of 30 minutes, wpbei by the simultaneous addition of triethylamine pH was maintained between 7.5 and 8.0. The mixture was stirred at 0 ° C. for 30 minutes and then as long as at room temperature until no addition of triethylamine to maintain the pH of 7.5 more was required. Now 130 Vol.Tle. Water added and the tetrahydrofuran largely removed in a rotary evaporator at room temperature. The remaining aqueous solution was shaken out once with ether, then covered with a layer with 300 Vol. Ethyl acetate, cooled to OoC and added with stirring and ice cooling with so much dilute hydrochloric acid that a pH of 1.5-2.0 was discontinued. The organic phase was separated off and the aqueous phase was extracted Suspension again with about 300 parts by volume of ethyl acetate and combined the organic Extracts.

The penicillin, which is very sparingly soluble in ethyl acetate, which in the aqueous Phase was suspended, was filtered off with suction, carefully washed acid-free with ice water and dried in vacuo at about 1 torr over P2 ° 5.

Yield: 71 0 B-lactam content: 93% calculated: C 50.1 H 5.0 N 14.6 S 6.7 found: C 50.1 H 5.6 N 13.8 S 6.8 NMR signals at Ht = 0.9 (2 H), 2.35 (1 H), 2.6 (5H), 4.25 (dimethyl- (1H), 4.55 (2H), 5.7 (1H), 6.0-7.0 sulfoxide-d6 (4 H), 8.4 (3 H) and 8.55 ppm (3 H) as solvent) IR bands at 3380, 3230, 1784, 1728, 1687, 1639, 1520, 1375, 1219 and 735 cm (Fig. 1) The product contains after separation in the paper chromatogram and subsequent development with B. subtilis only one antibiotic component.

After adding about 2 parts by volume of the ethyl acetate extract. a 1 molar solution of sodium 2-ethylhexanoate in methanol-containing ether 0.45 part by weight

Isolate (2.6% of theory) of penicillin in the form of its sodium salt.

The free acid of penicillin can easily be replaced by conventional Convert the process into the chemotherapeutically usable salts. (See example 7).

B. l-chlorocarbonyl imidazolidone (2) For the vigorously stirred solution of 3.5 parts by weight Imidazolidone (2) prepared according to Fischer and Koch, Ann. 232, p. 224 (1886) in 50 vol. absolute tetrahydrofuran was added dropwise 4 wt.

Parts of phosgene in 10 parts by volume of absolute tetrahydrofuran in the course of 15 minutes to. The mixture was then stirred at 10 ° C. for 3 hours and then through the reaction mixture passed a stream of dry air to remove the hydrochloric acid formed and blow out any remaining phosgene. Now it was dried to dryness on a rotary evaporator in vacuo evaporated and the solid residue over concentrated sulfuric acid and at about Dried 12 torr.

Yield: 93%. Melting point = 1500 ° C. after recrystallization from acetone-pentane.

calculated; C 32.3 H 3.4 N 18.8 C1 23.9 found: C 32.3 H (4.5) N 18.7 C1 23.9 NMR signals at ff = 5.7 to 6.1 (2 H) and 6.3 to 6.7 (2 H), (acetone-d6 as solvent) symmetrical A2B2 system IR bands at 3230, 1790, 1700, 1270 and 1150 cm.

Example 2 If, in the procedure of example 1, that there is replaced D - aminobenzylpenicillin used by 0.04 moles of α-amino-p-methylbenzylpenicillin each, α-amino-p-chlorobenzylpenicillin, α-amino-p-methylthiobenzylpenicillin, α-aminocc- (2) thienyl-methylpenicillin or cc-amino-a- (3) thienylmethylpenicillin the following penicillins are obtained: α- (imidazolidin-2-on-1-yl-carbonylamino) -p-methylbenzylpenicillin, a- (Imidazolidin-2-on-1-yl-carbonylamino) -p -chlorobenzylpenicillin, 0'- (Imidazolidin-2 -on-l-yl-carbonylamino) -pmethylthiobenzylpenicillin, cc- (Imidazolidin-2-on-l-ylcarbonylamino) -α- (2) thienylmethylpenicillin or α- (imidazolidin-2-on-1-yl-carbonylamino) -a- (3) thienylmethylpenicillin.

Example 3 If, in the procedure of example 1, that there is replaced used l-chlorocarbonyl-imidazolidone by in each case 0.035 mol of 1-chlorocarbonyl-1,3-diazacyclohexan-2-one, l-chlorocarbonyl-1,3-diazacycloheptan-2-one, 1-chlorocarbonyl-5-methylimidazolidone (2), l-chlorocarbonyl-4-methyl-imidazolidone (2), 1-chlorocarbonyl-5,5-dimethyl-imidazolidone (2), 1-chlorocarbonyl-4,4-dimethyl-imidazolidine (2), 1-chlorocarbonyl-4,5-cisdimethyl-imidazolidone (2), l-chlorocarbonyl-4,5-trans-dimethylimidazolidone, l-chlorocarbonyl-benzimidazolone, l-chlorocarbonyl-6-methyl-benzimidazolone, l-chlorocarbonyl-5-methylbenzimidazolone, l-chlorocarbonyl-4-methyl-benzimidazolone, l-chlorocarbonyl-7-methylbenzimidazolone, l-chlorocarbonyl-5-nitrobenzimidazolone, l-chlorocarbonyl-6-nitro-benzimidazolone, l-chlorocarbonyl-hexahydrobenzimidazolone (2), l-chlorocarbonyl-6-aza-benzimidazolone, l-chlorocarbonyl-5-aza-benzimidazolone, l-chlorocarbonyl-5-carbethoxy-benzimidazolone, l-chlorocarbonyl-6-carbethoxy-benzimidazolone and 2-chlorocarbonyl-2,4-diazabicyclo [3,2,2] nonan-3-one, the following are obtained Penicillins: D - «- (1,3-Diazacyclohexan-2-on-1-yl-carbonylamino) -benzylpenicillin, D-α- (1,3-diazacycloheptan-2-on-1-yl-carbonylamino) -benzylpenicillin, D-α-5-methylimidazolidin-2-on-1-yl-carbonylamino) -benzylpenicillin, D-a- (4-methylimidazolidin-2-on-1-yl-carbonylamino) -bnzylpenicillin, D-α- (5,5-dimethylimidazolidin-2-on-1-yl-carbonylamino) -benzylpenicillin, D-a- (4,4-Dimethylimidazolidin-2-on-1-yl-carbonylamino) -benzylpenicillin, D-α- (4,5-cis-dimethylimidazolidin-2-on-1-yl-carbonylamino) -benzylpenicillin, D-α- (4,5-trans-dimethylimidazolidin-2-on-1-yl-carbonylamino) -benzylpenicillin, D-α- (Benzimidazolin-2-on-1-yl-carbonylamino) -benzylpenicillin, D-a- (6-methylbenzimidazolin-2-on-l-ylcarbonylamino) -benzylpenicillin, D-α-5-methylbenzimidazolin-2-on-1-yl-carbonylamino) -benzylpeniclline, D-α- (4-methylbenzimidazolin-2-on-1-yl-carbonylamino) -benzylpenicillin, D - «- (7-methylbenzimidazolin-2-on-1-yl-carbonylamino) -benzylpenicillin, D-α- (5-nitrobenzimidazolin-2-on-1-ylcarbonylamino) -benzylpenicillin, D-α- (6-nitrobenzimidazolin-2-on-1-yl-carbonylamino) -benzylpenicillin, D-α- (hexahydrobenzimidazolin-2-on-1-yl-carbonylamino ) -benzylpenicillin, D-a- (6-azabenzimidazolin-2-on-1-yl-carbonylamino) -benzylpenicillin, D-α- (5-azabenzimidazolin-2-one-1-ylcarbonylamino) -benzylpenicillin, D-α- (5-carbethoxybenzimidazolin-2-on-1-yl-carbonylamino) -benzylpenicillin, D - «- (6-Carbethoxybenzimidazolin-2-on-1-yl-carbonylamino) -benzylpenicillin, or D-α- (2,4-Diazabicyclo [3, 2, 27nonan-3-on-2-yl-carbonylamino) -benzylpenicillin.

EXAMPLE 4 A. D-cc- (Imidazolidin-2-thion-l-yl-carbonylamino) -benzylpenicillin-sodium: 8, 5 parts by weight of l-chlorocarbonyl-imidazolidin-2-thione were at OOC and pH 7.5 to 8.0 (glass electrode) with stirring with 17.5 parts by weight. D-α-aminobenzylpenicillin in 170 vol.

Tln. 80% aqueous tetrahydrofuran implemented. To maintain triethylamine was gradually added to the pH. It was at room temperature Stirred until it was no longer necessary to add triethylamine to the To keep pH at 7.5 .. Then you added 150 Vol.Tle. Water to, provided with a little dilute hydrochloric acid a pH of 6.5 and pulled in a rotary evaporator Room temperature from the tetrahydrofuran. Now the was extracted once with ether The aqueous phase is covered with a layer of 300 parts by volume of ethyl acetate, cooled to 0 ° C. and below Stirring and cooling with ice, dilute hydrochloric acid is added up to a pH of 1.5 to 2.0. The organic phase was separated off and the aqueous solution was extracted again with 300 Vol. Tln. Ethyl acetate and combined the organic solutions, which then were dried with MgSOX.

On the addition of about 40 ml of a 1 molar solution of sodium 2-ethylhexanoate The sodium salt of penicillin precipitated in methanol-containing ether. From the suspension most of the ethyl acetate was stripped off in vacuo, the residue in methanol dissolved and to a mixture of 300 vol.

Parts of ether and 30 parts by volume of methanol were added dropwise. From the failed After standing for a short time, the ether / methanol mixture was decanted off and the product Product worked through several times with ether. They sucked off and dried over P205 in a vacuum desiccator.

Effectiveness against psdm. aerug. Bonn: 25 U / ml effectiveness against Proteus 3400: 50 U / ml Yield: 40% P-lactam content: 90% (due to the ß-lactam band of the IR spectrum estimated) NMR signals at # = 2.3 to 2.8 (5 H), 4.4 (1 H), 4.55 (2 H), (methanol-d4 5.85 (1 H), 6.0 to 6.5 (4 H), 8.4 (3 H), as solution) and 8.5 ppm (3 H).

medium) IR bands at 3320, 1760, 1720, 1665, 1602, 1520, 1365, and 1255 cm1 of B. l-trimethylsilyl-imidazolidin-2-thione: 30.6 parts by weight. Imidazolidine-2-thione were with 54.4 wt.

Parts of trimethylchlorosilane and 51.5 parts by weight. Triethylamine in absolute Tetrahydrofuran boiled overnight. The warm suspension was from the precipitated Triethylamine hydrochloride filtered, the filtrate evaporated and in a vacuum desiccator dried. Melting point: approx. 1300 ° C. Yield 97 β calculated: N 14.4 S 16.5 found: N 13.8 S 16.9 Strong Si-C stretching vibration in the IR spectrum at 850 cm 1.

C. 1-chlorocarbonyl-imidazolidine-2-thione: 50 parts by weight. l-trimethylsilyl-imidazolidine-2-thione were in 150 vol. Dichloromethane with 35 parts by weight. Phosgene in 50 parts by volume. Dichloromethane Added in the course of 2 hours at 0 ° C., the mixture was stirred for 24 hours at 0 ° C., then drew the dichloromethane and-dried the residue in a high vacuum. Semi-solid, in acetone incompletely soluble mass.

Crude yield: 97% IR bands at 1830, 1590 and 1240 cml Example 5 If in the manner described in Example 4A 17.5 parts by weight. Ampicillin with 0.05 mol each of l-chlorocarbonyl-l, 3-diazacyclohexane-2-thione, l-chlorocarbonyl-4-methylimidazolidine-2-thione, l-chlorocarbonyl-5-methylimidazolidine-2-thione, l-chlorocarbonyl4,4-dimethylimidazolidine-2-thione, 1-chlorocarbonyl-5,5-dimethylimidazolidine-2-thione or 1-chlorocarbonyl-4,5-dimethylimidazolidine-2-thione in order to obtain the following penicillins in the form of their sodium salts: D-α- (1,3-diazacyclohexan-2-thion-1-yl-carbonylamino) -benzylpenicillin, D-α- (4-methylimidazolidin-2-thion-1-yl-carbonylamino) -benzylpenicillin, D-α- (5-methylimidazolidin-2-thionl-yl-carbonylamino) -benzylpenicillin, D-a- (4,4-Dimethylimidazolidin-2-thion-1-yl-carbonylamino) -benzylpenicillin, D- «- (5,5-Dimethylimidazolidin-2-thion-1-yl-carbonylamino) -benzylpencillin and D-α- (4,5-dimethylimidazolidin-2-thion-1-yl-carbonylamino) -benzylpenicillin, respectively.

Example 6 In the procedure of Example 4, A is substituted for of the D-or-aminobenzylpenicillin used there, each 0.05 mol of α-amino-p-methylbenzylpenicillin, α-amino-p-chlorobenzylpenicillin, α-amino-p-methylthiobenzylpenicillin, α-amino-α- (2) -thienylmethylpenicillin and α-amino-α- (3) thienylmethylpenicillin, respectively, the following are obtained Penicillins in the form of their sodium salts: α- (Imidazolidin-2-thion-1-yl-carbonylamino) -p-methylbenzylpenicillin, α- (Imidazolidin-2-thion-1-yl-carbonylamino) -pchlorobenzylpenicillin, α- (Imidazolidin-2-thion-1-yl-carbonylamino) -p-methyltio-benzylpenicillin, α- (Imidazolidin-2-thion-1-yl-carbonylamino) -cc- (2) thienylmethylpenicillin respectively.

a- (Imidazolidin-2-thion-1-yl-carbonylamino) -a- (3) thienylmethylpenicillin.

Example 7 A. D-cc- (Imidazolidin-2-on-1-yl-carbonylamino) -benzylpenicillin-sodium.

5.5 parts by weight of D-α- (imidazolin-2-on-1-yl-carbonylamino) -benzylpenicillin, which had been obtained moist with water according to the information in Example 1, were in 13 vol. Dimethylacetamide dissolved with ice cooling and then with 10 vol. Part.

a 1 molar solution of sodium 2-ethylhexanoate in methanol-containing Aether displaced. The resulting clear solution was added dropwise within a few Minutes to a cold mixture of 200 Vol.Tln. Aether and 20 Vol.Tln.

Methanol, being the sodium salt of penicillin as fine-grained precipitate deposited, which was suctioned off and rinsed thoroughly with anhydrous Ether was washed.

Yield: 81% based on the 1-chlorocarbonylimidazolin-2-one used.

P-lactam content: 90% ~ (due to the intensity of the p-lactam carbonyl band of the IR spectrum).

IR bands at 3290, 1770, 1715, 1647, 1538 and 1276 cm -1.

(IR spectrum in Nujol). (Fig. 2) B. Crystallized D-α- (Imidazolidin-2-on-1-yl-carbonylamino) -benzylpenicillin-sodium: 0.4 part by weight of the product of Example 7 A were in 0.5 Vol.Tln. Clear water. One added 1.3 parts by volume.

Ethanol and slowly diluted while shaking with 3.0 parts by volume. Ethyl acetate. From the initially clear solution, 0.2 parts by weight crystallized overnight. D-or- (Imidazolidin-2-on-l-yl-carbonylamino) -benzylpenicillin-sodium in the form of-clusters fine needles.

Decomposition range: 200 - 2200C IR bands at 3370, 3225, 1775, 1728, 1688, 1640 and 1275 cm (Fig. 3) The following figures show for comparison the IR spectra of D-cc- (imidazolidin-2-on-l-yl-carbonylamino) -benzylpenicillin as free acid, as amorphous and as crystallized sodium salt.

Claims (11)

Patent claims: Penicillins of the general formula I: where A is a group E is oxygen or sulfur, Q is a divalent group of the type: C) 0 or 1,2,3 or 4, t-4C) or 1 C (C) 1 or 2 G p and g = 0,1,2 or 3 # # p + g = 1, 2 or 3 G or 1 o = CI (¢) O or 1 C <Ü GGGG HG p and g = 0 or ß p + g iP + = 0 or 1 'P-fC f- R1 wherein G is hydrogen or lower alkyl, Rt and Ra hydrogen, nitro, nitrile, di-lower alkylamino, di-lower alkylaminocarbonyl, lower alkanoylamino, lower alkoxycarbonyl, lower alkanoyloxy, lower alkyl, lower alkoxy, sulfamyl, chlorine, bromine, iodine, fluorine or trifluoromethyl, the arrow in the divalent group to express that the connection of the two free valences of with the two N atoms of the group not arbitrarily, but in the manner indicated by the arrow, M is a group \ Y'2,3,4 or 5 GEG ip e iQ rp LP + g = 2 or 3 years + g = 2 or the 2nd a GE means B denotes phenyl or phenyl or thienyl substituted by lower alkyl, lower alkoxy, lower alkylthio or halogen, and which, with respect to the center of chirality, can be in the two possible R and S configurations and as mixtures of the diastereomers resulting therefrom. non-toxic, pharmaceutically acceptable salts. 2) Compounds according to claim 1, in which the group A is. 3) Compounds according to claim 1, in which the group A is. 4) Compounds according to claim 1, in which B is phenyl. 5) Compounds according to claim 1, in which C * in the R configuration is present. 6) D-x- t <imidazolidin-2-on-1-yl) -carbonyl-amino7-benzyl penicillin and its non-toxic, pharmaceutically acceptable salts. 7) D-α- [(Imidazolidin-2-thion-1-yl) -carbonyl-amino] -benzylpenicillin and its non-toxic, pharmaceutically acceptable salts. 8) Use of the penicillins according to claim 1 as antibacterial Middle. 9) Use of the penicillins according to claim 1 as a medicament in of human medicine. 10) Medicines characterized by a content of penicillins according to claim 1. 11) Process for the preparation of compounds of the general formula I: where A is a group E is oxygen or sulfur, Q is a divalent group of the type: GGEG or 4, (C) O or or 1 1'1,2, or 4 1 -C Eq IG p and g = 0, 1, 2 or 3 p G LP L + g = 1, 2 or 3 G L / O or 1 i / 0 or GGG C- CG M / T 8 GG C p "in and g = 0 or 1 pp + g = 0 or ~ GG 1 R2 where G is hydrogen or lower alkyl, R1 and Ra hydrogen, nitro, nitrile, di-lower alkylamino,, oin lower alkylaminocarbonyl, lower alkanoylamino, lower alkoxycarbonyl, lower alkanoyloxy, lower alkyl, lower alkoxy, sulfamyl, chlorine, bromine, iodine, fluorine or trifluoromethyl, the arrow in the divalent group to express that the connection of the two free valences of with the two N atoms of the group not arbitrarily, but in the manner indicated by the arrow, M is a group G t ct 1/2 or 5 G EG ^ 3p E (t pound g = 0, 1 or 2 [p + g = 2 or 3 denotes, B denotes phenyl or phenyl or thienyl substituted by lower alkyl, lower alkoxy, lower alkythio or halogen, and the two possible R and S with respect to the center of chirality C * -Configurations and as mixtures of the resulting diastereomers, characterized in that compounds of the general formula II or condensation products of compounds of general formula II with carbonyl compounds such as acetone (USA Patent No. 3,198,804), of general formula III or compounds of the general formulas IV and V where B and G have the meaning given above and R *, R5 and R6 are alkyl with up to 6 carbon atoms, with compounds of the general formula VI in which E and Q have the meaning given above and W is halogen or azide, in the case of using the compounds of the general formulas II and III in anhydrous or water-containing solvents in the presence of a base, in the case of using the compounds of the general formulas IV and V in anhydrous and hydroxyl group-free solvents with or without the addition of a base at a temperature in the range from about -200C to + 500C to implement.